As compounds possessing gastrointestinal tract contraction-promoting activity, the erythromycin derivatives, N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal and N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal are described in Japanese Patent Unexamined Publication Nos. 99092/1988 (EP-A-0215355) and 99016/1988 (EP-A-0215355). These two patent publications disclose a method of producing N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal by N-isopropylating N-demethyl-8,9-anhydroerythromycin A-6,9-hemiacetal, and a method of producing N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal by treating N-demethyl-N-ethyl-erythromycin A with glacial acetic acid to form a 6,9-hemiacetal ring.
These two patent publications also disclose a method of purifying said desired compounds by silica gel column chromatography.
For N-alkylation reaction of N-demethylerythromycin A, however, alkyl groups having 3 or more carbon atoms (e.g., propyl, isopropyl, butyl, isobutyl etc.), especially branched alkyl groups (e.g., isopropyl, isobutyl etc.), are difficult to introduce, though alkyl groups having 1 to 2 carbon atoms (i.e., methyl, ethyl) are easy to introduce. In addition, yield is low due to the formation of a large amount of byproducts. These are problematic for a process for industrial mass production. The method of producing N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal described in the above-mentioned Japanese Patent Unexamined Publication Nos. 99092/1988 and 99016/1988 is therefore unpractical as an industrial process.
Also, the method wherein N-demethyl-N-ethyl-erythromycin A is treated under acidic conditions to yield N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal, described in the above-mentioned Japanese Patent Unexamined Publication Nos. 99092/1988 and 99016/1988, is problematic as an industrial process because the starting material N-demethyl-N-ethyl-erythromycin A and the resulting product N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal are both difficult to purify.
Moreover, the method of purifying the desired compound by silica gel column chromatography disclosed in these two patent publications poses some problems, including (i) a lot of time is required to operate such chromatographic treatment and concentrate the eluants after chromatography on an industrial mass scale, and (ii) silica gel is expensive material and difficult to recycle, its use resulting in massive waste. There has therefore been a need for a simple production method of the desired product at high purity and high yield on an industrial mass scale.